HomeDendritic Spine Loss in Alzheimer Disease: Role of Caspase Cleavage of the Amyloid Precursor Protein (APP)

A Novel Mechanism of Neuronal Disconnection in Early Stage Alzheimer’s

Goonho Park, PhD

University of California, San Diego (La Jolla, CA)

Year Awarded:

2018

Grant Duration:

July 1, 2018
to
June 30, 2020

Disease:

Alzheimer's Disease

Award Amount:

$150,000

Grant Reference ID:

A2018212F

Award Type:

Postdoctoral Fellowship

Award Region:

US Southwestern

Dendritic Spine Loss in Alzheimer Disease: Role of Caspase Cleavage of the Amyloid Precursor Protein (APP)

Summary

Neurons communicate one another by forming synapses in brain. For reasons that are not completely clear, these synaptic connections are susceptible to damage and are lost in the early stages of AD. Injury and loss of synapses in the brain are believed to be a major reason for cognitive impairment seen in individuals with AD. Amyloid-beta peptide (Aβ), which is generated from amyloid precursor protein (APP), is hypothesized to be one of the major reasons for synaptic damage. In addition, however, APP also generates another fragment called C31 which we hypothesize could play an additional role in synaptic injury. In this project, we will test whether blocking C31’s generation from APP can protect synapses from injury and damage.

Details

With aging, overall brain function is declining; with Alzheimer’s and other neurodegenerative diseases, patients are also losing their most cherished memories. Through my research, I hope to explain the underlying mechanism behind the aging of the brain and neuronal death. Of several theories to explain the pathomechanism of Alzheimer’s disease (AD), the amyloid cascade hypothesis currently guides our understanding; however, interventions suggested by this framework have thus far all failed to be clinically effective. Therefore, we still need to know more details about AD’s pathomechanism. Our study will look at the toxicity of amyloid beta (Aβ) and the other amyloid precursor protein (APP)-derived fragments, an area that has been difficult to thoroughly understand because of the lack of successful purification of some of the peptide fragments. In this study, we will genetically explore a modified mouse model and a novel virus system expressing Aβ in order to determine the correlation between the APP fragmentation and AD. I hope that designing effective therapeutics for AD may be made more precise by this investigation.

About the Researcher

My journal in scientific training is a little unusual and longer than the typical individual. I have been fortunate to be involved in biomedical research for the past eighteen years through research assistantships and training positions in both South Korea and the United States. These opportunities have given me ample experience and perspective to come to the decision to focus on age-associated neurodegenerative diseases, a topic that hope I will make important contributions to in the future.

Professionally trained in cell and molecular biology in both Korea and in the U.S., I have worked in brain diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and traumatic brain injury, for eight years as a predoctoral and postdoctoral researcher. I began my scientific training first in the private sector by choosing to pursue the “industrial research for Korean” option in lieu of military service required of all South Korean male citizens. During this time, I worked in both a biotechnology and a pharmaceutical company. I acquired experience in protein chemistry while working on the development of recombinant hepatitis A type virus vaccine, as well as molecular biology techniques in a team that generated eight knock-in and knockout mouse lines. These experiences ignited my interest in basic and translational biomedical research. It also enabled me to return to the academic setting, first as a research associate at Caltech in Dr. Melvin I. Simon’s lab and later at the University of California, San Diego (UCSD), when his lab relocated there. From there, I enrolled as a graduate student at the Sanford Burnham Medical Research Institute to focus on neurological diseases, especially age-related brain disorders, as I had become fascinated by how neuronal dysfunction leads to aberrant behavior. My PhD project was to examine neurodegeneration in dopaminergic neurons caused by abnormal histone modification, and how this may relate to Parkinson’s disease. This was an epigenetic approach to understanding neurodegenerative disease. Upon graduation in the fall of 2014, I joined Dr. Koo’s lab at UCSD for postdoctoral training. My current research project, as outlined in this proposal, is to study the pathological role of the C-terminal fragment of the amyloid precursor protein (APP) and how this might contribute to synaptic dysfunction and synapse loss in Alzheimer’s disease. I believe this investigation may reveal new insights into the process of synapse loss associated with not only AD, but age-dependent cognitive impairment in other neurodegenerative diseases as well. I am hopeful that successfully carrying out the proposed studies will be a big step towards launching my career as an independent neuroscientist focusing on neurodegenerative brain disorders.

Personal Story

My mother was the most influential person in my life, a constant presence always steadying and supporting me. When she passed away, I fell down into deep grief and it really brought home the fact that nobody can escape the aging process or dying itself, which is one of the clearest phenotypes in biology, as immutable as Newton’s first law. Although it may be conditional on many factors, unlike the laws of physics, and that variation makes it harder to understand, there should be some underlying mechanism to describe the phenotype, I love looking for the answers to how brain aging is processed or structured, as I am personally inspired and motivated by a strong curiosity. I am especially interested in the question of how neurons die in the aging brain. Understanding more about Aβ-dependent neurodegeneration is essential to finding a cure for Alzheimer’s disease. The new findings from this proposal would be supportive to discover therapeutic cures for AD patients. In the middle of my journey, it is an honor to be together with the BrightFocus Foundation and its philanthropists, and I would like to express my sincere appreciation for your lofty sacrifice and commitment.